This invention relates to certain long chain saturated and monounsaturated fatty acid derivatives of 2xe2x80x2,2xe2x80x2-difluoro-deoxycytidine (Gemcitabine), and to pharmaceutical compositions containing them. Gemcitabine has the 5 formula: 
Gemcitabine is a nucleoside analogue which has shown effect for the treatment of neoplastic conditions in both in vitro and in in vivo studies. (New anticancer agents, Weiss et al, Cancer Chemotherapy and Biological Response Modifiers Annual 16, editors Pinedo, Longo and Chabner, 1996. Elsevier Science B. V., Supplement to Seminars in Oncology, Vol. 22, No. 4, Suppl. 11, 1995, editors Yarbro et al. Gemcitabine Hydrochloride: Status of Preclinical Studies). A beneficial effect has also been observed in the clinical development of Gemcitabine. In these studies both the clinical and side effects of Gemcitabine are highly schedule dependent. (Seminars in Oncology, Vol. 22, No. 4, Suppl. 11, 1995, pp 42-46).
Gemcitabine is activated inside the cell by deoxycytidine kinase to its active form, the triphosphate of Gemcitabine (dFdCTP). Parallel to this Gemcitabine is deactivated by deoxycytidine deaminase to the corresponding uracil derivative (inactive).
We have now surprisingly found that certain fatty acid derivatives of Gemcitabine have a totally altered pharmacokinetics and tissue distribution. Especially will this be the case with malignant diseases in the RES, lungs, pancreas, intestines, esophagus, uterus, ovaries, melanoma and mammae.
The compounds of the present invention can be represented by the formula I: 
wherein R1, R2 and R3 are independently selected from hydrogen and C18- and C20-saturated and monounsaturated acyl groups, with the proviso that R1, R2 and R3 cannot all be hydrogen.
Gemcitabine has three derivatisable functions, namely the 5xe2x80x2- and 3xe2x80x2-hydroxyl groups and the N4xe2x88x92 amino group. Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well. In the case of the di-and tri-adducts the acyl substituent groups need not necessarily be the same.
Currently, the mono-acyl derivatives of this invention, i.e. with two of R1, R2 and R3 being hydrogen, are preferred. It is especially preferred that the monosubstitution with the acyl group should be in the 3xe2x80x2-O and 5xe2x80x2-O positions of the sugar moiety, with 5xe2x80x2-O substitution being most preferred.
The double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
The position of the double bond in the monounsaturated acyl groups also seem to affect the activity. Currently, we prefer to use esters or amides having their unsaturation in the xcfx89-9 position. In the xcfx89-system of nomenclature, the position xcfx89 of the double bond of a monounsaturated fatty. acid is counted from the terminal methyl group, so that, for example, eicosenoic acid (C20:1xcfx89-9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain. We prefer to use esters, ester-amides and amides derived from oleic acid (C18:1xcfx89-9, cis), elaidic acid (C18:1xcfx89-9, trans), eicosenoic acid(s) (C20:1xcfx89-9, cis) and (C20:1xcfx89-9, trans), and the amides and 5xe2x80x2-esters are currently the most preferred derivatives of this invention.
Esters, ester-amides and amides of Gemcitabine derived from stearic acid (C18:0) and eicosanoic acid (C20:0) are advantageously used in some cases.
The derivatives of Gemcitabine according to this invention may generally be prepared according to the following reaction equation: 
wherein Nuxe2x80x94YH stands for Gemcitabine, Y is oxygen at the 3xe2x80x2 and/or 5xe2x80x2 position of the sugar moiety or nitrogen at the 4 position of the pyrimidine moiety of Gemcitabine, Fa is an acyl group of a monounsaturated C18 or C20 fatty acid, and X is a leaving group, for example Cl, Br, 3-thiazolidine-2-thione or ORxe2x80x2 wherein Rxe2x80x2 is Fa, COCH3, COEt or COCF3. Thus, the reaction proceeds by acylation of the nucleoside. This is accomplished by the use of suitable reactive derivatives of fatty acids, especially acid halides or acid anhydrides.
Generally, a proton scavenger needs to be present in order to mop up the acid HX which is liberated by the reaction. Thus, a base may be added to the reaction mixture. For example, when an acid halide such as an acid chloride is used, a tertiary amine base, such as triethylamine, N,N-dimethylaniline, pyridine or N,N-dimethylaminopyridine can be added to the reaction mixture to bind the liberated hydrohalic acid. In other cases, a solvent used in the reaction may serve as the proton scavenger.
Normally, the acylation reaction proceeds without the need for a catalyst. The reactive fatty acid derivative FaX may, in some cases, be formed in situ by means of coupling reagents such as N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide (EDC) or O-(1H-benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate(TBTU).
The reactions are preferably carried out in an unreactive solvent such as N,N-dimethylformamide or a halogenated hydrocarbon, such as dichloromethane. If desired any of the above mentioned tertiary amine bases may be used as solvent, taking care that a suitable excess is present. In this case a separate proton scavenger is not needed. The reaction should preferably be kept between 5xc2x0 C. and 25xc2x0 C. After a period of 1 to 60 hours, the reaction will be essentially completed. The progress of the reaction can be followed using thin layer chromatography (TLC) and appropriate solvent systems. When the reaction is completed as determined by TLC, the product can be extracted with an organic solvent and purified by chromatography and/or recrystallization from an appropriate solvent system. As more than one hydroxyl group and also an amino group are present in Gemcitabine, a mixture of acylated compounds may be produced. If required, the individual mono- and multi-acylated derivatives required may be separated by, for instance, chromatography, crystallization, supercritical extraction, etc.
When it is desired to prepare a multi-acyl compound of formula I, in which R1 and/or R2 and/or R3 are the same acyl group, it is preferred to employ the above method(s) using the appropriate acyl-reagent(s) in excess.
In order to prepare multi-acyl compounds of formula I, in which R1 and/or R2 and/or R3 are different, it is preferred to employ the above methods in a stepwise manner with the appropriate choice of reagent. It is also possible to employ properly chosen protecting groups to ensure a specific reaction. A selection of these methods is shown in Scheme 1 below. Any combination of the methods may be employed to prepare a specific product. 